Chronic kidney disease (CKD) is still a major global health problem, with approximately 697.5 million people worldwide were reported to have CKD in 2017, of which 1.2 million people died due to CKD.1 Hyperphosphatemia is often found in CKD. Declined renal function, particularly in the advanced stage will lead to serum phosphate accumulation due to an inability to excrete serum phosphate which mostly originates from daily intestinal absorption. Osteocytes then release fibroblast growth factor 23 (FGF23) in order to promote renal phosphate excretion. Unfortunately, FGF23 also impair renal 1.25-dihydroxycalcitriol production which disturb intestinal calcium absorption, resulting in hypocalcemia. Parathyroid glands then release parathyroid hormone (PTH) as a compensatory mechanism to increase serum calcium through bone resorption. Calcium and phosphate release from destructed bone will lead to cardiovascular calcification and bone disorders, thus increasing morbidity and mortality in patients with CKD.2,3

Dialysis, phosphate binders, and calcimimetic agents are available modalities for hyperphosphatemia management in CKD, but they still have some disadvantages including flexibility limitation, hypocalcemia risk, as well as metal overload and cardiovascular calcification.4–6 Tenapanor is a novel modality option for hyperphosphatemia in CKD with its mechanism which inhibit sodium-hydrogen exchanger isoform 3 (NHE3) in gastrointestinal tract. This new medication has also been indicated for irritable bowel syndrome with constipation (IBS-C).7,8 In this review, we provide clinical evidences of the effectivity and safety profile of tenapanor in managing hyperphosphatemia in CKD through its NHE3 inhibition.

Literature searching was performed in Pubmed and Science Direct by using “tenapanor”, “chronic kidney disease”, and “hyperphosphatemia” as keywords. The studies then systematically selected by using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) algorithm (Fig. 1). Duplicate literatures were removed. Review articles, books, conferences abstracts, editorials, commentaries, letter to editor, and guidelines were excluded, while research studies were retrieved. Literature screening was performed by using Population, Intervention, Comparison, and Outcome (PICO) criteria which are: CKD patients requiring dialysis as population, tenapanor or its combination with dialysis or phosphate binders as intervention, placebo or other phosphate binders without tenapanor as comparison, as well as serum phosphate and safety profile as the outcome. Studies which meet the criteria then examined for risk of bias as quality assessment and qualitatively synthesized to establish this systematic review.

Fig. 1.

Literature screening algorithm by using “The Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) version 2020.

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Phosphate retention is frequently found in CKD stage 4 and 5, which is a factor that initiate many other disturbances such as increased FGF23 and PTH, hypocalcemia, and low vitamin D, which in turn will lead to an enhancement in cardiovascular and all causes of morbidity and mortality.18 Phosphate balance is maintained by several mechanism including intestinal phosphate absorption, bone turnover regulation, as well as renal excretion and reabsorption.4,19 In a normal condition, the kidney excretes approximately ninety percent of phosphate per day.20 As renal phosphate clearance declined in CKD, inhibiting intestinal phosphate absorption can be a promising approach in managing hyperphosphatemia in patients with CKD.4,20

Generally, phosphate binders only result in maximum 2.0mg/dL of phosphate reduction in their maximal doses.9 Some of our included studies show that 30mg of tenapanor whether as fixed or titrated dose single therapy was able to reduce serum phosphate up to more than 2.0mg/dL.9,10 This finding can be possible due to tenapanor mechanism which suppress intestinal phosphate absorption through NHE3 inhibition,9–11,14 as about 90% of phosphate input comes from intestinal absoption.20

Tenapanor works by inhibiting NHE3 which then interferes with sodium and phosphate absorption in the intestinal lumen. By using this mechanism, tenapanor has a promising potency to effectively treat hyperphosphatemia in CKD due to its dominant role in gastrointestinal tract, as around 90% of phosphate are originated from intestinal absorption.9–11

Our included studies which used tenapanor as monotherapy commonly revealed a dose-dependent phosphate lowering effect.9–12 Tenapanor 1mg BID showed serum phosphate declined up to −1.18mg/dL.10,12 Administration frequency also influence the effectivity of tenapanor 3mg, which reduce serum phosphate around −1.28mg/dL in once daily dose10 and up to −2.48mg/dL in BID dose.9,10 Tenapanor 10mg BID was shown to reduced serum phosphate up to −2.52mg/dL in several studies.9–12 Tenapanor with dose of 30mg also showed the same frequency-dependent manner in lowering serum phosphate, where twice daily dose resulted in up to −2.67mg/dL serum phosphate reduction, while in once daily dose, the serum phosphate only decreased up to −1.85mg/dL.10 In the other hand, 30mg BID tenapanor with dose titration exhibited an unsignificant difference in phosphate reduction effect compared to non-dose-titration administration of tenapanor 30mg.9,10 This finding suggest the possible strategy to achieve the highest serum phosphate reduction target by using tenapanor with optimum dose while minimizing the side effects by using dose-titration strategy.9,10

Unlike the studies that used tenapanor as monotherapy, the phosphate reduction trend is inconsistent with the dose in studies that used tenapanor in combination with other phosphate binders. Tenapanor 30mg BID in combination with the patient's pre-existing phosphate binders resulted in −0.84mg/dL phosphate reduction in a study by Pergola et al.13 and −1.5mg/dL reduction in a study by Shigematsu et al.14 Meanwhile, in the study by Nitta et al., tenapanor 5mg BID in combination with patient's pre-existing phosphate binder reduced the serum phosphate up to −2.0mg/dL,15 which was even higher than tenapanor 30mg BID in studies by Pergola et al.13 and Shigematsu et al.14 This different trend can be possibly caused by the effect of other phosphate binders which could probably have any undiscovered interactions with tenapanor. Further studies which analyze the possible drug-drug interaction between tenapanor and other phosphate binders is needed to explore the exact possible results of combination therapy between tenapanor and other phosphate binders as hyperphosphatemia therapy for patients with CKD. However, until the time of this review is conducted, studies show that tenapanor as monotherapy has a better phosphate reduction effect compared to tenapanor as a combination therapy with other phosphate binders.9–15

Serum phosphate after the termination of tenapanor is also one of the concerns. In randomized withdrawal period in the study by Block et al. in 2019, patients receiving placebo for 4 weeks after the last dose of tenapanor experienced increasing serum phosphate of only +0.79mg/dL.9 In the study by Block et al. in 2017, the follow-up visit at 1–2 weeks after the last dosage of tenapanor showed that the serum phosphate of all groups were between 3 and 6mg/dL which still didn’t reach the baseline serum phosphate before the beginning of intervention.10 In addition, a study by Inaba et al. revealed that serum phosphate levels were increased near baseline levels in follow-up visit after 3 weeks from the last dosage of tenapanor.11 These findings suggest that serum phosphate maintenance after the last dosage of tenapanor can be variable, which could be possibly influenced by several factors such as the baseline serum phosphate which varies in these studies, duration since the last dosage of tenapanor which only 1–2 weeks in certain studies and up to 4 weeks in the other study, also the dosage and frequency of tenapanor administration, which implies the need for further studies to examine serum phosphate maintenance in more detailed period after the last dosage of tenapanor. However, from these studies, it can be concluded that serum phosphate can still be maintained at levels below the baseline, even until 3–4 weeks after the last dosage of tenapanor.9–11

In addition to its phosphate lowering effect, tenapanor was also found to have a pleiotropic effect in suppressing the levels of FGF23 and PTH, both as monotherapy and combination therapy with phosphate binders.10–13,15,16 The exact mechanism of this finding remains unclear, but it can be possibly explained by the role of these two hormones as compensatory mechanism to elevated serum phosphate, thus greater reduction of serum phosphate will suppress FGF23 and PTH production.9,11,12,15 This pleiotropic effect of tenapanor can be utilized to minimize the morbidity and mortality in CKD, as high FGF23 and PTH will cause extraosseous calcium and phosphate deposition, particularly in the heart valves and vascular. This condition then develop to valve and vascular atherosclerosis through osteochondrogenic differentiation and elastin degradation, leading to increased mortality due to cardiovascular disease.21 Besides that, increased PTH which enhance calcium efflux from bones is the cause of bone mass loss in patients with CKD, resulting in increased morbidity.22 Therefore, the pleiotropic effect of tenapanor in lowering FGF23 and PTH suggesting its potency as future treatment for bone mineral disease and secondary hyperparathyroidism in CKD.

Diarrhea is the most common AE caused by tenapanor. However, majority of reported diarrhea was transient and mild to moderate in intensity.13–15 This side effect appears as the effect of tenapanor mechanism which selectively inhibit the NHE3 in enterocytes, thus suppress the passive transport of phosphate in the intestine. Simultaneously, NHE3 inhibition also suppress intestinal sodium absorption which enhance sodium and water secretion in the intestinal tract.10,11 Elevated sodium, phosphate, and water content in the intestine then lead to loose stool and increased bowel movement which manifested as diarrhea.9,15 The incidence of diarrhea due to tenapanor has a higher trend in higher doses.9–15 Diarrhea side effect of tenapanor is no longer surprising, as tenapanor has also been indicated to treat IBS-C by its mechanism to increase water content in the intestinal lumen and stools. Utilization of tenapanor in IBS-C has been considered as safe and has been recommended by the American Gastroenterological Association (AGA) guideline.7,8,23 Dose titration can be a good solution for this problem to increase patient's compliance, as titrated dose of tenapanor 30mg BID exhibited a lower incidence of diarrhea while maintaining the same efficacy in reducing serum phosphate and FGF23 compared to fixed dose of tenapanor 30mg BID.11

Minerals deposition and metabolic disturbances are the other concerns in treatment options for hyperphosphatemia in CKD. Available phosphate binders still has systemic mineral and metabolic disadvantages, such as calcium accumulation and increased calcification in calcium based phosphate binders, potential nervous system toxicity in aluminum based phosphate binders, iron overload in iron based phosphate binders, fat-soluble vitamins deficiency and acidosis risk in sevelamer based phosphate binders, as well as possible lanthanum deposits in lanthanum based phosphate binders.4–6 Tenapanor comes as a solution to counteract these limitations, as tenapanor didn’t cause any meaningful changes in serum calcium, laboratory parameters, ECG, and physical examination.9–11,13,14 The plausible explanation for this finding is the nature of tenapanor as a calcium free non-metal phosphate reducer, thus it doesn’t cause calcium and metal accumulation. In addition, tenapanor is also a minimally absorbed molecule, resulting in minimum systemic side-effect.9,10

In conclusion, tenapanor, as a single therapy or in combination with phosphate binders, was effective in managing hyperphosphatemia in CKD. It also has pleiotropic effects in interfering high FGF23 and PTH thus exhibit a promising potency to treat secondary hyperparathyroidism in CKD. Diarrhea is the most common AE but it's only transient, dose-related, and mild to moderate in severity. Starting tenapanor with a low dose can be a solution for diarrhea side effect. Tenapanor doesn’t cause any meaningful change in ECG, serum calcium, and other laboratory and clinical parameters. Generally, tenapanor is safe and well-tolerated in CKD patients.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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